MicroRNAs (miRNAs) are small (approximately 21-24 nucleotides in length, these are also known as “mature” miRNA), non-coding RNA molecules encoded in the genomes of plants and animals. These highly conserved, endogenously expressed RNAs are believed to regulate the expression of genes by binding to the 3′-untranslated regions (3′-UTR) of specific mRNAs. MiRNAs may act as key regulators of cellular processes such as cell proliferation, cell death (apoptosis), metabolism, and cell differentiation. On a larger scale, miRNA expression has been implicated in early development, brain development, disease progression (such as cancers and viral infections). There is speculation that in higher eukaryotes, the role of miRNAs in regulating gene expression could be as important as that of transcription factors. More than 200 different miRNAs have been identified in plants and animals (Ambros et al., Curr. Biol., 2003, 13, 807-818). Mature miRNAs appear to originate from long endogenous primary miRNA transcripts (also known as pri-miRNAs, pri-mirs, pri-miRs or pri-pre-miRNAs) that are often hundreds of nucleotides in length (Lee, et al., EMBO J., 2002, 21(17), 4663-4670).
In mammals, only a few miRNAs have been assigned any function, although they are predicted to regulate a large percentage of genes, with estimates based on bioinformatic target prediction ranging as high as 30% (Lewis et al., 2005). Based on the early studies in invertebrates, miRNAs are expected to have similar roles in developmental regulation and cell differentiation in mammals, and roles for miRNAs in cardiogenesis (Zhao et al., 2005) and lymphocyte development (Chen et al., 2004) have been demonstrated. Several studies have also found a strong connection between miRNA and human cancer, including a report that miRNA genes are often found in genomic regions linked to cancer (Calin et al., 2004; McManus, 2003) and a study correlating miRNA expression profiles with developmental lineage and differentiation state of tumors (Lu et al., 2005). A potential role for miRNAs in metabolic pathways has been suggested by studies implicating miRNAs in regulation of adipocyte differentiation (Esau et al., 2004) and glucose-stimulated insulin secretion from pancreatic islet cells (Poy et al., 2004). miR-122a is expressed in the developing liver (Chang et al., 2004) and at high levels in the adult liver, where it makes up 70% of all miRNA (Chang et al., 2004; LagosQuintana et al., 2002). It is one of many tissue-specific microRNAs thought to be important for establishing patterns of gene expression which may be responsible for maintaining the differentiated state of a tissue (Lagos-Quintana et al., 2002; Lim et al., 2005). miR-122a was also reported to enhance replication of HCV through a novel mechanism which is not yet understood, making it also a potential therapeutic target for HCV infection (Jopling et al., 2005).
It is described herein that the modulation of miR-122a is an attractive approach for diseases and conditions characterized by elevated serum cholesterol, elevated serum triglycerides, or hepatic steatosis. The present invention therefore provides antisense compounds and methods useful for modulating miR-122a, to achieve clinically desirable changes in cholesterol and lipid profiles in animals.